Aryl spirohydantoin CGRP receptor antagonists

ABSTRACT

The present invention is directed to compounds that are antagonists of CGRP receptors and that are useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US2004/007686, filedMar. 10, 2004, which claims priority from U.S. Ser. No. 60/454,917,filed Mar. 14, 2003.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

CGRP is a potent vasodilator that has been implicated in the pathologyof cerebrovascular disorders such as migraine and cluster headache. Inclinical studies, elevated levels of CGRP in the jugular vein were foundto occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990,28, 183–187). CGRP activates receptors on the smooth muscle ofintracranial vessels, leading to increased vasodilation, which isthought to be the major source of headache pain during migraine attacksLance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines andNitric Oxide, Lippincott-Raven Publishers, 1997, 3–9). The middlemeningeal artery, the principle artery in the dura mater, is innervatedby sensory fibers from the trigeminal ganglion which contain severalneuropeptides, including CGRP. Trigeminal ganglion stimulation in thecat resulted in increased levels of CGRP, and in humans, activation ofthe trigeminal system caused facial flushing and increased levels ofCGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988,23, 193–196). Electrical stimulation of the dura mater in rats increasedthe diameter of the middle meningeal artery, an effect that was blockedby prior administration of CGRP(8-37), a peptide CGRP antagonist(Williamson et al., Cephalalgia, 1997, 17, 525–531). Trigeminal ganglionstimulation increased facial blood flow in the rat, which was inhibitedby CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93–99). Electricalstimulation of the trigeminal ganglion in marmoset produced an increasein facial blood flow that could be blocked by the non-peptide CGRPantagonist BIBN4096BS (Doods et al., Br. J. Pharmacol., 2000, 129,420–423). Thus the vascular effects of CGRP may be attenuated, preventedor reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245–247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614–624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261–1268; Edvinsson et al., Cephalalgia, 1994, 14,320–327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335–1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275–282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163–175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739–768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537–538;Salmon et al., Nature Neurosci., 2001, 4(4), 357–358); eye pain (May etal. Cephalalgia, 2002, 22, 195–196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30–36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260–265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchialhyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657,397–404; Schini et al., Am. J. Physiol., 1994, 267, H2483–H2490; Zhenget al., J. Virol., 1993, 67, 5786–5791); shock, sepsis (Beer et al.,Crit. Care Med., 2002, 30 (8), 1794–1798); opiate withdrawal syndrome(Salmon et al., Nature Neurosci., 2001, 4(4), 357–358) morphinetolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342–2351); hotflashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz etal., J. Urology, 2001, 166, 1720–1723); allergic dermatitis (Wallengren,Contact Dermatitis, 2000, 43 (3), 137–143); psoriasis; encephalitis,brain trauma, ischaemia, stroke, epilepsy, and neurodegenerativediseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15–34); skindiseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRCPress, Boca Raton, Fla.), neurogenic cutaneous redness, skinrosaceousness and erythema; tinnitus (Herzog et al., J. MembraneBiology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowelsyndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414–422) and cystitis. Of particular importance is the acuteor prophylactic treatment of headache, including migraine and clusterheadache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are antagonists ofCGRP receptors and which are useful in the treatment or prevention ofdiseases in which the CGRP is involved, such as migraine. The inventionis also directed to pharmaceutical compositions comprising thesecompounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   B is a selected from the group consisting of:    -   C₃₋₁₀cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl,        biphenyl, phenanthryl, anthryl, azepinyl, azetidinyl,        benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl,        benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,        benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl,        chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl,        dihydrobenzothienyl, dihydrobenzothiopyranyl,        dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,        imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,        isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,        morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,        4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,        2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,        piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,        pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,        tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl,        tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,        thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl,        thiazolinyl, thienofuryl, thienothienyl, thienyl and triazolyl,    -   where B is linked to A¹ via a carbon atom in B and    -   where B is unsubstituted or substituted with 1–5 substituents        where the substituents are independently selected from R¹, R²,        R^(3a) and R^(3b), wherein    -   R¹, R², R^(3a) and R^(3b) are independently selected from:        -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with            1–7 substituents where the substituents are independently            selected from:            -   (a) halo,            -   (b) hydroxy,            -   (c) —O—C₁₋₆alkyl,            -   (d) —C₃₋₆cycloalkyl,            -   (e) phenyl or heterocycle, wherein heterocycle is                selected from: pyridyl, pyrimidinyl, pyrazinyl,                pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                thienyl, or morpholinyl,            -    which is unsubstituted or substituted with 1–5                substituents where the substituents are independently                selected from:                -   (i) —C₁₋₆alkyl,                -   (ii) —O—C₁₋₆alkyl,                -   (iii) halo,                -   (iv) hydroxy,                -   (v) trifluoromethyl, and                -   (vi) —OCF₃,            -   (f) —CO₂R⁹, wherein R⁹ is independently selected from:                -   (i) hydrogen,                -   (ii) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1–6 fluoro,                -   (iii) —C₅₋₆cycloalkyl,                -   (iv) benzyl, and                -   (v) phenyl,            -   (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently                selected from:                -   (i) hydrogen,                -   (ii) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1–6 fluoro,                -   (iii) —C₅₋₆cycloalkyl,                -   (iv) benzyl,                -   (v) phenyl,                -   (vi) —COR⁹, and                -   (vii) —SO₂R¹²,            -   (h) —SO₂R¹², wherein R¹² is independently selected from:                -   (i) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1–6 fluoro,                -   (ii) —C₅₋₆cycloalkyl,                -   (iii) benzyl, and                -   (iv) phenyl,            -   (i) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are                independently selected from:                -   (i) hydrogen,                -   (ii) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1–6 fluoro,                -   (iii) —C₅₋₆cycloalkyl,                -   (iv) benzyl,                -   (v) phenyl,                -   or where R^(10a) and R^(11a) may be joined together                    to form a ring selected from azetidinyl,                    pyrrolidinyl, piperidinyl, piperazinyl, or                    morpholinyl, which is unsubstituted or substituted                    with 1–5 substituents where the substituents are                    independently selected from:                -    (I) —C₁₋₆alkyl                -    (II) —O—C₁₋₆alkyl                -    (III) halo                -    (IV) hydroxy                -    (V) phenyl, and                -    (VI) benzyl,            -   (j) trifluoromethyl,            -   (k) —OCO₂R⁹,            -   (l) —(NR^(10a))CO₂R⁹,            -   (m) —O(CO)NR^(10a)R^(11a), and            -   (n) —(NR⁹)(CO)NR^(10a)R^(11a),        -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1–7 substituents where the substituents are            independently selected from:            -   (a) halo,            -   (b) hydroxy,            -   (c) —O—C₁₋₆alkyl,            -   (d) trifluoromethyl,            -   (e) phenyl, which is unsubstituted or substituted with                1–5 substituents where the substituents are                independently selected from:                -   (i) —C₁₋₆alkyl,                -   (ii) —O—C₁₋₆alkyl,                -   (iii) halo,                -   (iv) hydroxy, and                -   (v) trifluoromethyl,        -   (3) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyriridinyl, pyrazinyl, thienyl, pyridazinyl,            pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl,            isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepinyl,            benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,            benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl,            indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,            isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl,            2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl,            pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl,            thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl,            quinazolinyl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl and            morpholinyl, which is unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from:            -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1–6 fluoro,            -   (b) halo,            -   (c) hydroxy,            -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1–6 fluoro,            -   (e) —C₃₋₆cycloalkyl,            -   (f) phenyl or heterocycle, wherein heterocycle is                selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl,                or morpholinyl,            -    which is unsubstituted or substituted with 1–5                substituents where the substituents are independently                selected from:                -   (i) —C₁₋₆alkyl,                -   (ii) —O—C₁₋₆alkyl,                -   (iii) halo,                -   (iv) hydroxy, and                -   (v) trifluoromethyl,            -   (g) —CO₂R⁹,            -   (h) —NR¹⁰R¹¹,            -   (i) —CONR¹⁰R¹¹, and            -   (j) —SO₂R¹²,        -   (4) halo,        -   (5) oxo,        -   (6) hydroxy,        -   (7) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1–5 halo,        -   (8) —CN,        -   (9) —CO₂R⁹,        -   (10) —NR¹⁰R¹¹,        -   (11) —SO₂R¹²,        -   (12) —CONR^(10a)R^(11a),        -   (13) —OCO₂R⁹,        -   (14) —(NR^(10a))CO₂R⁹,        -   (15) —O(CO)NR^(10a)R^(11a),        -   (16) —(NR⁹)(CO)NR^(10a)R^(11a),        -   (17) —SO₂NR^(10a)R^(11a), and        -   (18) —COR¹²;        -   or where R^(3a) and R^(3b) and the atom(s) to which they are            attached may be joined together to form a ring selected from            cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,            cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl,            tetrahydrofuranyl, tetrahydropyranyl, furanyl,            dihydrofuranyl, dihydropyranyl or piperazinyl, which is            unsubstituted or substituted with 1–5 substituents where the            substituents are independently selected from:            -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1–3 substituents where the substituents are                independently selected from:                -   (i) halo,                -   (ii) hydroxy,                -   (iii) —O—C₁₋₆alkyl,                -   (iv) —C₃₋₆cycloalkyl,                -   (v) phenyl or heterocycle, wherein heterocycle is                    selected from: pyridyl, pyirimdinyl, pyrazinyl,                    pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                    thienyl, or morpholinyl, which is unsubstituted or                    substituted with 1–5 substituents where the                    substituents are independently selected from:                -    (I) —C₁₋₆alkyl,                -    (II) —O—C₁₋₆alkyl,                -    (III) halo,                -    (IV) hydroxy,                -    (V) trifluoromethyl, and                -    (VI) —OCF₃,                -   (vi) —CO₂R⁹,                -   (vii) —NR¹⁰R¹¹,                -   (viii) —SO₂R¹²,                -   (ix) —CONR^(10a)R^(11a), and                -   (x) —(NR^(10a))CO₂R⁹,            -   (b) phenyl or heterocycle, wherein heterocycle is                selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl,                pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and                morpholinyl, which is unsubstituted or substituted with                1–3 substituents where the substituents are                independently selected from:                -   (i) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1–6 fluoro,                -   (ii) halo,                -   (iii) hydroxy,                -   (iv) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1–6 fluoro, and                -   (v) —C₃₋₆cycloalkyl,            -   (c) halo,            -   (d) —SO₂R¹²,            -   (e) hydroxy,            -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1–5 halo,            -   (g) —CN,            -   (h) —COR¹²,            -   (i) —NR¹⁰R¹¹,            -   (j) —CONR^(10a)R^(11a),            -   (k) —CO₂R⁹,            -   (l) —(NR^(10a))CO₂R⁹,            -   (m) —O(CO)NR^(10a)R^(11a), and            -   (n) —(NR⁹)(CO)NR^(10a)R^(11a);-   A¹ and A² are independently selected from:    -   (1) a bond,    -   (2) —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are independently selected        from:        -   (a) hydrogen,        -   (b) C₁₋₆ alkyl, which is unsubstituted or substituted with            1–6 fluoro, and        -   (c) hydroxy,    -   (3) NR¹⁰—, and    -   (4) —CR¹³R¹⁴—NR¹⁰—,    -   (5) —CR¹³R¹⁴—CH₂—,    -   (6) —CH₂—CR¹³R¹⁴—,    -   (7) —O—C R¹³R¹⁴—,    -   (8) —CR¹³R¹⁴—O—, and    -   (9) —C≡C—,    -   or wherein one of A¹ and A² is absent;-   X selected from —CO— and —SO₂—;-   R⁴ is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆ alkyl, which is unsubstituted or substituted with 1–6        fluoro,    -   (3) C₅₋₆ cycloalkyl,    -   (4) benzyl, and    -   (5) phenyl;-   R^(5a), R^(5b) and R^(5c) are independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆ alkyl,    -   (3) —O—C₁₋₆alkyl,    -   (4) —OCF₃,    -   (5) trifluoromethyl,    -   (6) halo,    -   (7) hydroxy, and    -   (8) —CN;-   R⁶ is selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl or —C₃₋₆cycloalkyl which are unsubstituted or        substituted with 1–7 substituents where the substituents are        independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl, which is unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from:            -   (i) —C₁₋₆alkyl,            -   (ii) —O—C₁₋₆alkyl,            -   (iii) halo,            -   (iv) hydroxy, and            -   (v) trifluoromethyl,        -   (f) —CO₂R⁹,        -   (g) —NR¹⁰R¹¹,        -   (h) —CONR¹⁰R¹¹,        -   (i) —SO₂R¹², and        -   (j) trifluoromethyl    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which        is unsubstituted or substituted with 1–5 substituents where the        substituents are independently selected from:        -   (a) —C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) hydroxy, and        -   (e) trifluoromethyl;-   m is 1 or 2;-   n is 1 or 2;    and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein B, A¹, A², R⁴, and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ib:

wherein B, R⁴ and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ic:

wherein B and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Id:

wherein B is defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ie:

wherein B, R⁴ and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula If:

wherein B and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ig:

wherein B is defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ih:

wherein B and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ii:

wherein B and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ij:

wherein B, R⁴ and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

In an embodiment of the present invention B is selected from the groupconsisting of: C₃₋₁₀cycloalkyl, phenyl, napthyl, tetrahydronaphthyl,indanyl, isoquinolinyl, morpholinyl, naphthyridinyl, piperidyl,piperazinyl, pyrazinyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl,pyrimidyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinoxalinyl,thiazolyl, and thienyl, which is unsubstituted or substituted with 1–5substituents selected from R¹, R², R^(3a) and R^(3b), wherein R¹, R²,R^(3a) and R^(3b) are defined herein.

In an embodiment of the present invention B is phenyl.

In an embodiment of the present invention B is thienyl.

In an embodiment of the present invention B is pyridyl.

In an embodiment of the present invention B is quinolinyl.

In an embodiment of the present invention B is quinoxalinyl.

In an embodiment of the present invention B is naphthyl.

In an embodiment of the present invention B is norbornyl.

In an embodiment of the present invention B is cyclohexyl.

In an embodiment of the present invention B is cyclopentyl.

In an embodiment of the present invention B is cyclopropyl.

In an embodiment of the present invention B is thiazolyl.

In an embodiment of the present invention B is indanyl.

In an embodiment of the present invention R¹, R², R^(3a) and R^(3b) areindependently selected from:

-   (1) C₁₋₆ alkyl,-   (2) C₃₋₆ cycloalkyl,-   (3) —O—C₁₋₆alkyl,-   (4) —OCF₃,-   (5) trifluoromethyl,-   (6) halo,-   (7) —CN,-   (8) —COR¹²,-   (9) —CO₂R¹²,-   (10) —CONR^(10a)R^(11a),-   (11) phenyl, which is unsubstituted or substituted with 1–5    substituents selected from:    -   (a) C₁₋₆alkyl,    -   (b) —O—C₁₋₆alkyl,    -   (c) halo,    -   (d) —OH, and    -   (e) —CF₃,-   (12) heterocycle, wherein heterocycle is selected from: pyridyl,    pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, piperidinyl or    morpholinyl, and which is unsubstituted or substituted with 1–5    substituents selected from:    -   (a) C₁₋₆alkyl,    -   (b) —O—C₁₋₆alkyl,    -   (c) halo,    -   (d) —OH, and    -   (e) —CF₃.

In an embodiment of the present invention A¹ is a bond.

In an embodiment of the present invention A¹ is —CH₂—.

In an embodiment of the present invention A¹ is —OCH₂—.

In an embodiment of the present invention A¹ is —C≡C—.

In an embodiment of the present invention A² is a bond.

In an embodiment of the present invention A² is —CH₂—.

In an embodiment of the present invention A² is —NH—.

In an embodiment of the present invention A² is —CH₂—NH—.

In an embodiment of the present invention X is —CO—.

In an embodiment of the present invention X is —SO₂—.

In an embodiment of the present invention R⁴ is hydrogen.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) areindependently selected from hydrogen, C₁₋₆alkyl and halo.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) arehydrogen.

In an embodiment of the present invention R⁶ is hydrogen or methyl.

In an embodiment of the present invention m is 1.

In an embodiment of the present invention n is 1.

In an embodiment of the present invention n is 2.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. The compounds of the instant invention have oneasymmetric center. Additional asymmetric centers may be presentdepending upon the nature of the various substituents on the molecule.Each such asymmetric center will independently produce two opticalisomers and it is intended that all of the possible optical isomers anddiastereomers in mixtures and as pure or partially purified compoundsare included within the ambit of this invention. The present inventionis meant to comprehend all such isomeric forms of these compounds.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include chloro, fluoro, bromo and iodo.Similarly, C₁₋₈, as in C₁₋₈alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branchedarrangement, such that C₁₋₈alkyl specifically includes methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl,heptyl and octyl. Likewise, C₀, as in C₀alkyl is defined to identify thepresence of a direct covalent bond. The term “heterocycle” as usedherein is intended to include, but is not limited to, the followinggroups: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will beunderstood that, as used herein, references to the compounds of FormulaI are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 3944). Briefly,membranes (25 μg) were incubated in 1 ml of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP andantagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 μl) was addedand the radioactivity was counted on a Topcount (Packard Instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochem. Pharmacol. 22, 3099–3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimalessential medium (MEM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/ml penicillin and 100 μg/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 μM isobutylmethylxanthine inserum-free MBM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 15 min, then the cells were washed with PBSand processed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 nM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48–58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIREShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession numberAJ001014) was subcloned into the expression vector pIRESpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLRand RAMP1 expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were diluted andselective medium (growth medium+300 ug/ml hygromycin and 1 ug/mlpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5ug/ml puromycin for cell propagation.

RECOMBINANT RECEPTOR BIDING ASSAY: Cells expressing recombinant humanCRLR/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:

$Y_{\underset{\_}{obsd}} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {\%\mspace{14mu} I_{\max -}\%\mspace{14mu}{I_{\min}/100}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\mspace{14mu}{I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$Where Y is observed CPM bound, Y_(max) is total bound counts, Y min isnon specific bound counts, (Y max−Y min) is specific bound counts, % Imax is the maximum percent inhibition, % I min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Coming) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human α-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K_(i) or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; encephalitis; braintrauma; epilepsy; neurodegenerative diseases; skin diseases; neurogeniccutaneous redness, skin rosaceousness and erythema; inflammatory boweldisease, irritable bowel syndrome, cystitis; and other conditions thatmay be treated or prevented by antagonism of CGRP receptors. Ofparticular importance is the acute or prophylactic treatment ofheadache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-inflammatory or analgesic agent or an anti-migraine agent, such asan ergotamine or 5-HT₁ agonists, especially a 5-HT_(1B/1D) agonist, forexample sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan; a cyclooxygenase inhibitor,such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidalanti-inflammatory agent or a cytokine-suppressing anti-inflammatoryagent, for example with a compound such as aspirin, ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or a steroidal analgesic.Similarly, the instant compounds may be administered with a painreliever such as acetaminophen, phenacetin, codeine, fentanyl,sufentanil, methadone, acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; a tricyclic antidepressant, for exampleamitriptyline, doxepin, protriptyline, desipramine, triripramine, orimipramine; a leukotriene antagonist, for example montelukast orzafirlukast; an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide.

Also, the present compounds may be used in conjunction with ergotalkaloids, for example ergotamine, ergonovine, ergonovine,methylergonovine, metergoline, ergoloid mesylates, dihydroergotamine,dihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine,ergocristine, ergocryptine, I-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol, ornadolol, and the like; a MAO inhibitor, for example phenelzine; acalcium channel blocker, for example flunarizine, nimodipine,lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin;neuroleptics such as olanzapine and quetiapine; an anticonvulsant suchas topiramate, zonisamide, tonabersat, carabersat or divalproex sodium;an angiotensin II antagonist, for example losartan and candesartancilexetil; an angiotensin converting enzyme inhibitor such aslisinopril; or botulinum toxin type A.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as phenylephrine, phenylpropanolamine,pseudoephedrine, oxymetazoline, epinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; anantitussive such as codeine, hydrocodone, caramiphen, carbetapentane, ordextromethorphan; a diuretic; a prokinetic agent such as metoclopramideor domperidone, and a sedating or non-sedating antihistamine.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: an ergotamine; a 5-HT₁agonist, especially a 5-HT_(1B/1D) agonist, in particular, sumatriptan,naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan,donitriptan and rizatriptan; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, meloxicam, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the compound of the presentinvention to the other active ingredient(s) may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with another agent, the weightratio of the compound of the present invention to the other agent willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia; and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Oral tablets may also beformulated for immediate release, such as fast melt tablets or wafers,rapid dissolve tablets or fast dissolve films.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, preferablygiven as a single daily dose or in divided doses two to six times a day,or in sustained release form. For most large mammals, the total dailydosage is from about 1.0 milligrams to about 1000 milligrams, preferablyfrom about 1 milligrams to about 50 milligrams. In the case of a 70 kgadult human, the total daily dose will generally be from about 7milligrams to about 350 milligrams. This dosage regimen may be adjustedto provide the optimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes.

The synthesis of spirohydantoin intermediates may be conducted asdescribed in Schemes 1–4. Spirohydantoin intermediates bearing R^(5a),R^(5b) and R^(5c) may be prepared by employing appropriately substitutedstarting materials or by derivatization of any intermediates and/orfinal products as desired by methods known in the art.

Commercially available 6-bromo-2-tetralone (1) may be readily convertedto the spirohydantoin 2 under Bucherer-Bergs conditions, using ammoniumcarbonate and either sodium cyanide or potassium cyanide. Other2-tetralones may be readily accessed using a variety of literaturemethods, such as the Friedel-Crafts reaction of arylacetyl chlorideswith ethene as described by Burckhalter and Campbell, J. Org. Chem., 26,4232 (1961), and converted to the corresponding spirohydantoinsanalogously. In Scheme 1, treatment of spirohydantoin 2 with ethylmagnesium bromide followed by tert-butyllithium effects metal-halogenexchange and the resulting aryllithium species is quenched with carbondioxide to give acid 3. A Schmidt reaction of 3 with hydrazoic acid maybe used to provide aniline 4, as reviewed by Wolff, Org. React., 3, 307(1946). Alternatively, a modified Curtius rearrangement using 3 anddiphenylphosphoryl azide according to the procedure of Yamada andcoworkers, Tetrahedron, 30, 2151 (1974), can provide aniline 4 viaeither its tert-butyl or benzyl carbamate derivatives.

In Scheme 2, treatment of 6-bromo-2-tetralone (1) with methylaminehydrochloride and potassium cyanide, followed by potassium cyanate andhydrochloric acid, provides the methylated hydantoin derivative 5.Analogous procedures to those described in Scheme 1 may be used toprovide acid 6 and aniline 7.

Scheme 3 illustrates a route to 7-substituted tetralin derivatives 10and 11. 3-Bromophenylacetic acid is converted to the corresponding acidchloride and this is subjected to Friedel-Crafts reaction with ethene,affording the 7-bromo-2-tetralone 9. This intermediate may be elaboratedusing the procedures described in Scheme 1 to provide the acid (10) andaniline (11).

Scheme 4 details the synthesis of the key indane-based spirohydantoinintermediates.

2-Indanone (12) is converted to the spirohydantoin 13 via Bucherer-Bergschemistry as shown. Treatment of 13 with nitric acid provides the5-nitroindane derivative 14, which may be reduced to the correspondinganiline 15 under catalytic hydrogenation conditions. Alternatively, atwo-step process can be employed to convert 2-indanone (12) into theN-methylspirohydantoin 16. Treatment of 12 with potassium cyanide andmethylamine hydrochloride affords an amino nitrile which is converted tothe spirohydantoin 16 using potassium cyanate and acetic acid.Subjection of 16 to the nitration-reduction sequence used for 13 leadsto the corresponding aniline 18, as detailed in Scheme 4.

Spirohydantoin intermediates may be resolved to give pure enantiomersusing techniques familiar to those skilled in the art. For example,chromatography of the nitro intermediate 17 on a ChiralPak AD column canbe used to provide the individual enantiomers (+)-17 and (−)-17, andthese enantiomers may be reduced to the corresponding anilines [(+)-18and (−)-18] by catalytic hydrogenation. Use of standard couplingprocedures using enantiomerically pure anilines affords the individualenantiomers of the final products. Resolution may be effected by othermethodologies, such as fractional crystallization of diastereomericsalts, and it may be carried out on other synthetic intermediates or onthe final products. Alternatively, an assymetric synthesis of a keyintermediate, such as an amino acid precursor of a spirohydantoin, couldbe used to provide an enantiomerically enriched final product.

Spirohydantoin aniline intermediates, such as those described in Schemes1–4, may be further elaborated by techniques familiar to one skilled inthe art to provide a wide variety of final products, for example amides,ureas, and sulfonamides, as shown in Scheme 5.

Thus, coupling of amine A with a carboxylic acid, RCO₂H, can be used togive amide B. Other standard coupling conditions may be employed in thesynthesis of such amides, such as use of an alternative coupling reagentlike PyBOP, or activation of the carboxylic acid as an acid anhydride oracid chloride. Reaction of aniline A with either an isocyanate orsulfonyl chloride may be used to provide the corresponding urea (C) orsulfonamide (D) as shown in Scheme 5. Urea C may also be synthesizedfrom aniline A and an appropriate amine (R′NH₂) by use of phosgene,1,1′-carbonyldiimidazole, 4-nitrophenyl chloroformate, or a similarreagent.

Most of the acids (RCO₂H), isocyanates (R′NCO), and sulfonyl chlorides(R″SO₂Cl) used to make the compounds of the present invention arereadily available. They may be obtained from commercial sources orsynthesized by methodology familiar to those skilled in the art and asdescribed in the chemical literature.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

(±)-6′-Carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

Step A.(±)-6′-Bromo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A stirred mixture of 6-bromo-2-tetralone (17.6 g, 78.2 mmol), sodiumcyanide (9.58 g, 195 mmol), and ammonium carbonate (97.7 g, 1.02 mol) inH₂O (100 mL) and EtOH (100 mL) was heated to 70° C. for 3 h, thenallowed to cool to ambient temperature. The precipitate was collected byfiltration and washed with H₂O (5×200 mL). Drying in vacuo afforded thetitle compound as a pale solid. MS: m/z=297 (M+1).

Step B.(±)-6′-Carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

To a stirred suspension of(±)-6′-bromo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(14.9 g, 50.5 mmol) in TBF (1.2 L), at −70° C., was added dropwise ethylmagnesium bromide (3.0 M in TBF, 51 mL, 152 mmol). The resulting mixturewas stirred for 10 min, then tert-butyllithium (1.7 M in pentane, 180mL, 305 mmol) was added dropwise over 30 min. Stirring was continued at−70° C. for 20 min, then additional tert-butyllithium (1.7 M in pentane,60 mL, 102 mmol) was added dropwise over 10 min. After a further 30 min,CO_(2 (g)) was bubbled into the reaction mixture until LCMS analysisindicated complete reaction. The mixture was allowed to warm slowly toambient temperature and the THF was removed in vacuo. The residue wassuspended in H₂O and the solution was adjusted to pH=1–2 by the additionof conc. hydrochloric acid, to a final volume of about 500 mL. Themixture was filtered and the isolated solid was washed with H₂O (4×100mL) then dried in vacuo. Trituration of this crude solid with EtOHprovided the title compound as a pale tan solid. MS: m/z=261 (M+1).

(±)-6′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

Step A.(±)-6′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A stirred mixture of(±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(described in Intermediate 1) (1.50 g, 5.76 mmol), and sodium azide (749mg, 11.53 mmol) in conc. H₂SO₄ (30 mL) was heated to 50° C. for 2 h,then allowed to cool to ambient temperature. The mixture was adjusted topH 8 by addition of 6 N aqueous NaOH and concentrated in vacuo toprecipitate a solid. The precipitate was collected by filtration andwashed extensively with H₂O. Drying in vacuo afforded the title compoundas a light brown solid. MS: m/z=232 (M+1).

(±)-6′-Carboxy-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

Step A.(±)-6′-Bromo-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A mixture of 6-bromo-2-tetralone (1.00 g, 4.44 mmol) and methylaminehydrochloride (300 mg, 4.44 mol) in H₂O (1 mL) and EtOH (1.5 mL) wasstirred at ambient temperature for 20 min. Potassium cyanide (289 mg,4.44 mmol) was added and stirring was continued for 18 h. The mixturewas added dropwise to a stirred solution of 1.0 N aqueous HCl (4.5 mL)at 0° C., then potassium cyanate (360 mg, 4.44 mmol) was addedportionwise. The stirred mixture was heated to 95° C. and conc.hydrochloric acid (0.44 mL) was added dropwise. The reaction mixture washeated at this temperature for 1 h, allowed to cool, and extracted withCH₂Cl₂ (80 mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated to dryness. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10 toprovide a crude sample of the title compound (ca. 70% pure). Triturationwith EtOH afforded the title compound as a pale solid. MS: m/z=311(M+1).

Step B.(±)-6′-Carboxy-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

To a stirred suspension of(±)-6′-bromo-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(211 mg, 0.682 mmol) in THF (30 mL), at −70° C., was added dropwiseethyl magnesium bromide (1.0 M in THF, 1.37 mL, 1.37 mmol). Theresulting mixture was stirred for 15 min, then tert-butyllithium (1.7 Min pentane, 1.61 mL, 2.73 mmol) was added dropwise. After a further 30min, CO_(2 (g)) was bubbled into the reaction mixture until LCMSanalysis indicated complete reaction. The mixture was allowed to warmslowly to ambient temperature and the THF was removed in vacuo. Theresidue was suspended in H₂O (20 mL) and the solution was adjusted topH=1–2 by the addition of 1.0 N hydrochloric acid, then it was saturatedwith NaCl _((s)). The mixture was filtered and the isolated solid waswashed with H₂O then dried in vacuo. Trituration of this crude solidwith EtOH provided the title compound as a pale tan solid. MS: m/z=275(M+1).

(±)-7′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

Step A. 7-Bromo-2-tetralone

A solution of 3-bromophenylacetic acid (10.4 g, 48.4 mmol) in oxalylchloride (50 mL, 0.57 mol) was stirred at ambient temperature for 5 minthen at reflux for 5 h. The oxalyl chloride was removed in vacuo and theresidue was dissolved in anhydrous CH₂Cl₂ (100 mL). This solution wasadded dropwise to a rapidly stirred, ice-cooled solution of AlCl₃ (23.2g, 174.2 mmol) in CH₂Cl₂ (500 mL). A stream of ethylene gas was blowninto the vortex of the stirred solution during the addition and thereaction temperature was kept at <5° C. The reaction mixture was allowedto warm to ambient temperature and then poured onto ice and stirredvigorously. The organic portion was removed and the aqueous layerextracted with CH₂Cl₂ (2×200 mL). The combined CH₂Cl₂ fractions werepassed through a 2″ pad of silica and concentrated to give a thick, redoil. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 75:25 to provide thetitle compound as a pale yellow solid. MS: m/z=226 (M+1).

Step B.(±)-7′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

Essentially following the procedures described for Intermediate 1 andIntermediate 2, but using 7-bromo-2-tetralone in place of6-bromo-2-tetralone,(±)-7′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dionewas prepared. MS: m/z=232 (M+1).

(±)-Spiro[imidazolidine-4,2′-indane]-2,5-dione

Step A. (±)-Spiro[imidazolidine-4,2′-indane]-2,5-dione

A stirred mixture of 2-indanone (3.0 g, 22.6 mmol), sodium cyanide (3.3g, 67.3 mmol), and ammonium carbonate (22 g, 228 mol) in H₂O (50 mL) andEtOH (50 mL) was heated to 70° C. for 3 h, then allowed to cool toambient temperature. The precipitate was collected by filtration andwashed with H₂O (5×100 mL). Drying in vacuo afforded the title compoundas a gray-brown solid. MS: m/z=202 (M+1).

(±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione

Step A. (±)-5′-Nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

A solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.0 g,14.8 mmol, described in Intermediate 40) in conc. nitric acid (33 mL)was stirred at ambient temperature for 1 h. The reaction was then pouredonto crushed ice and the resultant solid was isolated by filtration. Thecrude material was recrystallized from ethanol to give the titlecompound as a yellow solid. MS: m/z=248 (M+1).

Step B. (±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a suspension of(±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16mmol) in EtOAc (100 mL) and MeOH (100 mL) was added 10% Pd/C (400 mg)and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1h, the catalyst was filtered off and the filtrate was concentrated toyield the title compound as a pale brown solid. MS: m/z=218 (M+1).

(±)-5 ′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

Step A. 2-(Methylamino)indane-2-carbonitrile hydrochloride

To a mixture of 2-indanone (20.0 g, 151 mmol) in MeOH (20 mL) was addedmethylamine hydrochloride (10.2 g, 151 mmol). To the stirred mixture wasadded H₂O (20 mL) and a fine homogenous slurry developed. The reactionmixture was cooled to 0° C. and KCN (9.84 g, 151 mmol) in H₂O (20 mL)was added slowly over 30 min, such that the temperature did not exceed10° C., then stirring was continued at ambient temperature for 18 h. Thereaction mixture was extracted with Et₂O (250 mL) and the organicextract was washed with brine (50 mL) then dried over MgSO₄. HCl (g) wasbubbled through the vigorously stirred solution for 10 minutes and awhite solid precipitated. The solid was filtered, washed with Et₂O, anddried to yield the title compound. MS: m/z=173 (M+1).

Step B. (±)-3-Methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a stirred mixture of 2-(methylamino)indane-2-carbonitrilehydrochloride from Step A (6.0 g, 28.8 mmol) in AcOH (45 mL) was added asolution of potassium cyanate (4.65 g, 57 mmol) in H₂O (6 mL) and thereaction mixture was stirred for 1 h. The mixture was poured into coldH₂O (150 mL) and the precipitate was isolated by filtration, washed withH₂O and air dried. The crude solid was suspended in 1 N HCl (30 mL) andstirred to 50° C. for 2 h. The reaction mixture was cooled, filtered,and the isolated solid washed with H₂O and dried in vacuo to yield thetitle compound. MS: m/z=217 (M+1).

Step C. (±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

To stirred fuming nitric acid (100 mL) was slowly added(±)-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (4.5 g, 20.9mmol) in portions over 30 min. The reaction mixture was diluted with H₂O(200 mL) and the precipitate was collected by filtration, washed withH₂O and dried in vacuo to give the title compound. MS: m/z=262 (M+1).

Step D. (±)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

Essentially following the procedures described for Intermediate 6, butusing (±)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dionein place of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, thetitle compound was prepared. MS: m/z=232 (M+1).

(±)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

Step A. (±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

(±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione(described in Intermediate 7) was dissolved in a mixture of MeOH, CH₃CNand diethylamine and the enantiomers were resolved by HPLC, utilizing aChiralPak AD column and eluting with CH₃CN:MeOH—90:10. The first majorpeak to elute was(+)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione and thesecond major peak to elute was(−)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione. Thefirst major peak eluted was the title compound. MS: m/z=262 (M+1).

Step B. (+)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

Essentially following the procedures described for Intermediate 6, butusing (+)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dionein place of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, thetitle compound was prepared. MS: m/z=232 (M+1).

EXAMPLE 1

(±)-6′-[(3-Chlorobenzoyl)amino]-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A mixture of 3-chlorobenzoic acid (11 mg, 0.067 mmol),(±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(described in Intermediate 2) (13 mg, 0.056 mmol), EDC (13 mg, 0.067mmol), HOBT (10 mg, 0.067 mmol), and N,N-diisopropylethylamine (0.012mL, 0.067 mmol) was stirred in DMF (0.3 mL) at ambient temperature for18 h. The crude mixture was purified directly by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound as a white solid. MS: m/z=370 (M+1). HRMS: m/z=370.0957;calculated m/z=370.0953 for C₁₉H₁₇ClN₃O₃.

EXAMPLES 2–6

Essentially following the procedures outlined for Example 1, thecompounds listed in Table 1 were prepared. The requisite carboxylicacids were commercially available, described in the literature, orreadily synthesized by one skilled in the art of organic synthesis. Insome cases, straightforward protecting group strategies were applied.

TABLE 1

Example R^(b) MS (M + 1) 2

361 3

388 4

396 5

400 6

387

EXAMPLE 7

(±)-6′-{[(1-Naphthylamino)carbonyl]amino}-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A mixture of 1-naphthyl isocyanate (9.5 mg, 0.056 mmol),(±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dionehydrochloride (described in Intermediate 2) (15 mg, 0.056 mmol), andN,N-diisopropylethylamine (0.010 mL, 0.056 mmol) was stirred in THF (0.5mL) at ambient temperature for 18 h. The crude mixture was purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound as a white solid. MS: m/z=401 (M+1). HRMS: m/z=401.1638;calculated m/z=401.1608 for C₂₃H₂₁N₄O₃.

EXAMPLES 8–16

Essentially following the procedures outlined for Example 1, but usingIntermediate 6 in place of Intermediate 2, the compounds listed in Table2 were prepared. The requisite carboxylic acids were commerciallyavailable, described in the literature, or readily synthesized by oneskilled in the art of organic synthesis. In some cases, straightforwardprotecting group strategies were applied.

TABLE 2

Example R^(b) MS (M + 1) 8

362 9

350 10

342 11

382 12

413 13

419 14

362 15

415 16

447

EXAMPLES 17–27

Essentially following the procedures outlined for Example 7, but usingIntermediate 6 in place of Intermediate 2, the compounds listed in Table3 were prepared. The requisite isocyanates were commercially available,described in the literature, or readily synthesized by one skilled inthe art of organic synthesis.

TABLE 3

Example R^(b) MS (M + 1) 17

385 18

385 19

387 20

387 21

419 22

402 23

379 24

369 25

369 26

369 27

351

EXAMPLE 28

(±)-5′-(1-Naphthylsulfonyl)amino-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a stirred solution of 50 mg (0.23 mmol)(±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described inIntermediate 6) in THF (3 mL) was added 1-naphthalenesulfonyl chloride(53 mg, 0.24 mmol) and triethylamine (0.034 mL, 0.24 mmol). After 30 minthe reaction mixture was concentrated to dryness. The residue wasdissolved in DMF and purified by HPLC using a reversed phase C18 columnand eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound as a white solid. MS: m/z=408(M+1). HRMS: m/z=408.1019; calculated m/z=408.1013 for C₂₁H₁₇N₃O₄S.

EXAMPLES 29–37

Essentially following the procedures outlined for Example 1, but usingIntermediate 8 in place of Intermediate 2, the compounds listed in Table4 were prepared. The requisite carboxylic acids were commerciallyavailable, described in the literature, or readily synthesized by oneskilled in the art of organic synthesis. In some cases, straightforwardprotecting group strategies were applied.

TABLE 4

Example R^(b) MS (M + 1) 29

376 30

364 31

356 32

494 33

354 34

370 35

376 36

380 37

360

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above.

1. A compound of the formula I:

wherein: B is a selected from the group consisting of: C₃₋₁₀cycloalkylphenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl,anthryl, azepinyl, azetidinyl, benzimidazolyl, benzisoxazolyl,benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl,dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyland triazolyl, where B is linked to A¹ via a carbon atom in B and whereB is unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R¹, R², R^(3a) and R^(3b),wherein R¹, R², R^(3a) and R^(3b) are independently selected from: (1)—C₁₋₆alkyl, which is unsubstituted or substituted with 1–7 substituentswhere the substituents are independently selected from: (a) halo, (b)hydroxy, (c) —O—C₁₋₆alkyl, (d) —C₃₋₆cycloalkyl, (e) phenyl orheterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,or morpholinyl,  which is unsubstituted or substituted with 1–5substituents where the substituents are independently selected from: (i)—C₁₋₆alkyl, (ii) —O—C₁₋₆alkyl, (iii) halo, (iv) hydroxy, (v)trifluoromethyl, and (vi) —OCF₃, (f) —CO₂R⁹, wherein R⁹ is independentlyselected from: (i) hydrogen, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1–6 fluoro, (iii) —C₅₋₆cycloalkyl, (iv) benzyl, and (v)phenyl, (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selectedfrom: (i) hydrogen, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1–6 fluoro, (iii) —C₅₋₆cycloalkyl, (iv) benzyl, (v)phenyl, (vi) —COR⁹, and (vii) —SO₂R¹², (h) —SO₂R¹², wherein R¹² isindependently selected from: (i) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1–6 fluoro, (ii) —C₅₋₆cycloalkyl, (iii) benzyl, and(iv) phenyl, (i) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) areindependently selected from: (i) hydrogen, (ii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1–6 fluoro, (iii) —C₅₋₆cycloalkyl,(iv) benzyl, (v) phenyl, or where R^(10a) and R^(11a) may be joinedtogether to form a ring selected from azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted orsubstituted with 1–5 substituents where the substituents areindependently selected from:  (I) —C₁₋₆alkyl  (II) —O—C₁₋₆alkyl  (III)halo  (IV) hydroxy  (V) phenyl, and  (VI) benzyl, (j) trifluoromethyl,(k) —OCO₂R⁹, (l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), and (n)—(NR⁹)(CO)NR^(10a)R^(11a), (2) —C₃₋₆cycloalkyl, which is unsubstitutedor substituted with 1–7 substituents where the substituents areindependently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₆alkyl,(d) trifluoromethyl, (e) phenyl, which is unsubstituted or substitutedwith 1–5 substituents where the substituents are independently selectedfrom: (i) —C₁₋₆alkyl, (ii) —O—C₁₋₆alkyl, (iii) halo, (iv) hydroxy, and(v) trifluoromethyl, (3) phenyl or heterocycle, wherein heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, triazolyl, tetrazolyl, azepinyl, benzimidazolyl,benzopyranyl, benzofuryl, benzothiazolyl, benzoxazolyl, chromanyl,furyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl,pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl,purinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, 1,3-dioxolanyl,oxadiazolyl, piperidinyl and morpholinyl, which is unsubstituted orsubstituted with 1–5 substituents where the substituents areindependently selected from: (a) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1–6 fluoro, (b) halo, (c) hydroxy, (d) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1–6 fluoro, (e)—C₃₋₆cycloalkyl, (f) phenyl or heterocycle, wherein heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from: (i) —C₁₋₆alkyl, (ii)—O—C₁₋₆alkyl, (iii) halo, (iv) hydroxy, and (v) trifluoromethyl, (g)—CO₂R⁹, (h) —NR¹⁰R¹¹, (i) —CONR¹⁰R¹¹, and (j) —SO₂R¹², (4) halo, (5)oxo, (6) hydroxy, (7) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with 1–5 halo, (8) —CN, (9) —CO₂R⁹, (10) —NR¹⁰R¹¹, (11)—SO₂R¹², (12) —CONR^(10a)R^(11a), (13) —OCO₂R⁹, (14) —(NR^(10a))CO₂R⁹,(15) —O(CO)NR^(10a)R^(11a), (16) —(NR⁹)(CO)NR^(10a)R^(11a), (17)—SO₂NR^(10a)R^(11a), and (18) —COR¹²; or where R^(3a) and R^(3b) and theatom(s) to which they are attached may be joined together to form a ringselected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl orpiperazinyl, which is unsubstituted or substituted with 1–5 substituentswhere the substituents are independently selected from: (a) —C₁₋₆alkyl,which is unsubstituted or substituted with 1–3 substituents where thesubstituents are independently selected from: (i) halo, (ii) hydroxy,(iii) —O—C₁₋₆alkyl, (iv) —C₃₋₆cycloalkyl, (v) phenyl or heterocycle,wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, ormorpholinyl, which is unsubstituted or substituted with 1–5 substituentswhere the substituents are independently selected from:  (I) —C₁₋₆alkyl, (II) —O—C₁₋₆alkyl,  (III) halo,  (IV) hydroxy,  (V) trifluoromethyl,and  (VI) —OCF₃, (vi) —CO₂R⁹, (vii) —NR¹⁰R¹¹, (viii) —SO₂R¹², (ix)—CONR^(10a)R^(11a), and (x) —(NR^(10a))CO₂R⁹, (b) phenyl or heterocycle,wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl andmorpholinyl, which is unsubstituted or substituted with 1–3 substituentswhere the substituents are independently selected from: (i) —C₁₋₆alkyl,which is unsubstituted or substituted with 1–6 fluoro, (ii) halo, (iii)hydroxy, (iv) —O—C₁₋₆alkyl, which is unsubstituted or substituted with1–6 fluoro, and (v) —C₃₋₆cycloalkyl, (c) halo, (d) —SO₂R¹², (e) hydroxy,(f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1–5 halo,(g) —CN, (h) —COR¹², (i) —NR¹⁰R¹¹, (j) —CONR^(10a)R^(11a), (k) —CO₂R⁹,(l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), and (n)—(NR⁹)(CO)NR^(10a)R^(11a); A¹ and A² are independently selected from:(1) a bond, (2) —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are independentlyselected from: (a) hydrogen, (b) C₁₋₆ alkyl, which is unsubstituted orsubstituted with 1–6 fluoro, and (c) hydroxy, (3) NR¹⁰—, and (4)—CR¹³R¹⁴—NR¹⁰—, (5) —CR¹³R¹⁴—CH₂—, (6) —CH₂—CR¹³R¹⁴—, (7) —O—CR¹³R¹⁴—,(8) —CR¹³R¹⁴—O—, and (9) —C≡C—, or wherein one of A¹ and A² is absent; Xselected from —CO— and —SO₂—; R⁴ is selected from: (1) hydrogen, (2)C₁₋₆ alkyl, which is unsubstituted or substituted with 1–6 fluoro, (3)C₅₋₆ cycloalkyl, (4) benzyl, and (5) phenyl; R^(5a), R^(5b) and R^(5c)are independently selected from: (1) hydrogen, (2) C₁₋₆ alkyl, (3)—O—C₁₋₆alkyl, (4) —OCF₃, (5) trifluoromethyl, (6) halo, (7) hydroxy, and(8) —CN; R⁶ is selected from: (1) hydrogen, (2) —C₁₋₆alkyl or—C₃₋₆cycloalkyl which are unsubstituted or substituted with 1–7substituents where the substituents are independently selected from: (a)halo, (b) hydroxy, (c) —O—C₁₋₆alkyl, (d) —C₃₋₆cycloalkyl, (e) phenyl,which is unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from: (i) —C₁₋₆alkyl, (ii)—O—C₁₋₆alkyl, (iii) halo, (iv) hydroxy, and (v) trifluoromethyl, (f)—CO₂R⁹, (g) —NR¹⁰R¹¹, (h) —CONR¹⁰R¹¹, (i) —SO₂R¹², and (j)trifluoromethyl (3) phenyl or heterocycle, wherein heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl,which is unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from: (a) —C₁₋₆alkyl, (b)—O—C₁₋₆alkyl, (c) halo, (d) hydroxy, and (e) trifluoromethyl; m is 1 or2; n is 1 or 2; and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.
 2. The compound ofclaim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 3. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 4. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 5. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 6. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 7. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 8. The compound of claim 1 wherein B isselected from the group consisting of: C₃₋₁₀cycloalkyl, phenyl, napthyl,tetrahydronaphthyl, indanyl, isoquinolinyl, morpholinyl, naphthyridinyl,norbornyl, piperidyl, piperazinyl, pyrazinyl, pyridazinyl, pyridinyl,pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, quinazolinyl, quinolinyl,quinoxalinyl, thiazolyl, and thienyl, which is unsubstituted orsubstituted with 1–5 substituents selected from R¹, R², R^(3a) andR^(3b).
 9. The compound of claim 1 wherein R¹, R², R^(3a) and R^(3b) areindependently selected from: (1) C₁₋₆ alkyl, (2) C₃₋₆ cycloalkyl, (3)—O—C₁₋₆alkyl, (4) —OCF₃, (5) trifluoromethyl, (6) halo, (7) —CN, (8)—COR¹², (9) —CO₂R¹², (10) —CONR^(10a)R^(11a), (11) phenyl, which isunsubstituted or substituted with 1–5 substituents selected from: (a)C₁₋₆alkyl, (b) —O—C₁₋₆alkyl, (c) halo, (d) —OH, and (e) —CF₃, (12)heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl,pyrazinyl, thienyl, pyrrolidinyl, piperidinyl or morpholinyl, and whichis unsubstituted or substituted with 1–5 substituents selected from: (a)C₁₋₆alkyl, (b) —O—C₁₋₆alkyl, (c) halo, (d) —OH, and (e) —CF₃.
 10. Acompound selected from:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 11. A pharmaceutical composition whichcomprises an inert carrier and the compound of claim
 1. 12. A method oftreating migraine headaches or cluster headaches, said method comprisingthe administration, to a person in need of such treatment, of atherapeutically effective amount of the compound of claim 1.